Weekly administration of (bi-)daily Oral Docetaxel in combination with Ritonavir

Oral administration has many advantages above intravenously administrated drugs
for patients. However, oral bioavailability of docetaxel IV-solution is
frequently low and variable. The bioavailability of docetaxel is limited due to
metabolising cytochrome P450 (CYP) enzymes, which are abundantly present in the
gastrointestinal tract. Inhibition of CYP3A4 enzymes with ritonavir (an
anti-retroviral drug) has proven to enhance the bioavailability of oral
docetaxel in several trials.

The department of pharmacy of the Slotervaart HospitalSlotervaart Hospital
Slotervaart Hospital and Netherlands Cancer Institute developed a solid oral
dosage form for docetaxel, ModraDoc001 10 mg capsules. This formulation has now
been investigated in more than 40 patients in a first clinical study.
Currently, a dose escalation study of weekly administration (once daily) of
oral docetaxel (as ModraDoc001 10 mg capsules) in combination with ritonavir is
in progress at the NKI. The preliminary results of this study are promising and
a linearity between systemic exposure to docetaxel and the applied dose of
ModraDoc001 10 mg capsules is seen. In an attempt to further improve and
prolong the systemic exposure we will explore a twice daily dosing schedule.
This assessment will be done in arm A of this study with a classical dose
escalation design, starting with the highest daily administration which is
proven tolerable in the comparable dose escalation study (i.e. 40 mg BID).

The department of pharmacy developed recently two other novel dosage forms for
docetaxel, ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets. Both are
spray dried solid dispersions of docetaxel pressed in tablets. The distinction
between both is that ritonavir is included in the co-formulation of
ModraDoc004 10/50 mg tablets. Both dosage forms will be investigated in arm B
to see whether these new formulations have comparable pharmacokinetic
characteristics of docetaxel to the capsule formulation.

Oral administration of docetaxel has proven to be feasible in arm A. The MTD is
determined as 20 mg docetaxel as ModraDoc001 capsules in combination with 100
mg ritonavir BID. However, the production process of the capsule formulation is
labor intensive and therefore not suitable for possible phase II trials. Based
on the results of arm B, which has showed no significant differences in
exposure between ModraDoc001 10 mg capsules and ModraDoc003 10 mg tablets, the
department of pharmacy of the Slotervaart hospital developed an improved tablet
formulation. This new formulation, ModraDoc005 tablets, will be investigated in
an additional dose finding cohort (arm C) to determine the toxicity profile and
the pharmacokinetics.
ModraDoc006 tablets, will be investigated in an additional dose finding cohort
(arm D) to determine the toxicity profile and the pharmacokinetics. This arm is
added because of dissapointing bioavailability of the ModraDoc005 tablets.

The primary objective is to determine the maximum tolerated dose (MTD) of
docetaxel (as ModraDoc001) that can safely be administered to patients with
cancer in a bi-daily weekly schedule.

Arm A:
The optimal dose of bi-daily docetaxel in combination with ritonavir will be
determined with a classical dose escalation design. On a predefined day of the
first and every subsequent week, the patient will receive oral docetaxel (as
ModraDoc001 10 mg capsules), dosed according to the escalation schedule (see
*Dose escalation*) and ritonavir. This regime will be continued weekly (intake
around the same time) until progressive disease or until adverse events, which
require dose modification or discontinuation of therapy, are observed.
Three patients will be assigned to each dose level. If one patient of the first
three at a defined dose level experiences dose limiting toxicity (DLT), the
number of patients treated at this dose level will be expanded to a maximum of
six. The dose escalation will continue if none of the additional patients
experiences a DLT. The MTD level will be expanded to at least six patients.

The first dose level was not tolerable for two of the five patients. Although
only one of the two patients had a formal DLT, the dose level of 40 mg
docetaxel BID was not proven to be safe and tolerable. Therefore the next dose
level will be 20 mg docetaxel BID (equals 40 mg per week). If this dose level
is proven safe and tolerable, dose escalation will proceed to 30 mg docetaxel
BID. The dose of ritonavir will remain 100 mg BID (equals 200 mg on one
day/week).

Arm B:
Both new oral dosage forms, ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg
tablets, will be investigated to see whether these new formulations have
comparable pharmacokinetic characteristics of docetaxel when given as
ModraDoc001 10 mg capsules. Six evaluable patients will be randomized in a way
that all possible treatment regimes are given. The patients will receive 40 mg
docetaxel (as ModraDoc001 10 mg capsules, ModraDoc003 10 mg tablets and
ModraDoc004 10/50 mg tablets) and 200 mg ritonavir once daily (a week).
Patients continue in Week 4 with 80 mg ModraDoc001 10 mg capsules in
combination with 100 mg ritonavir once daily in a weekly schedule until
progressive disease or adverse events, which require dose modifications or
discontinuation of therapy, are observed. Patients should take the ModraDoc001
10 mg capsules, ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets in
the morning on an empty stomach (This means at least 2 hours of fasting before
intake of ModraDoc and after intake at least 1 hour before a breakfast can be
taken). ModraDoc001 10 mg capsules and ModraDoc003 10 mg tablets will be
administered simultaneously with 200 mg ritonavir. The docetaxel dose during
the first three weeks will be 40 mg.

Arm C:
The design of this part of the study is comparable with arm A. ModraDoc005
tablets will be investigated to determine the toxicity profile and the
pharmacokinetics. The starting dose will be 20mg docetaxel and 100 mg ritonavir
BID (dose level 2 of arm A), since this dose was the maximum tolerated dose
with capsules in arm A. Docetaxel and ritonavir are administered on a
predefined day of each week. This schedule will be continued weekly until it is
no longer in the patient*s best benefit. The dose level will start with three
patients. If none of the patients has experienced a DLT, a new dose level may
be started according to the percentages of the escalation rules of arm A. If
one patient has experienced a DLT, the dose level will be expanded to six
patients. If still less than two patients (out of six) have experienced a DLT,
a new dose level may be started according to the percentages of the escalation
rules of arm A. If two patients have experienced a DLT, a new dose level will
be started with a lower dose of docetaxel (to be determined by the principal
investigator after careful evaluation of safety and PK of the actual dose
level). Every dose level can be expanded to six patients, if less than 2 DLTs
have occurred. The final recommended dose for future phase II will be expanded
to a maximum of twelve patients.

Arm D:
The design of this part of the study is comparable with arm A. ModraDoc006
tablets will be investigated to determine the toxicity profile and the
pharmacokinetics. This arm was added because of low bio-availability of the
ModraDoc005 tablets. The starting dose will be 20 mg docetaxel and 100 mg
ritonavir BID (dose level 2 of arm A), since this dose was the maximum
tolerated dose with capsules in arm A. Docetaxel and ritonavir are administered
on a predefined day of each week. This schedule will be continued weekly until
it is no longer in the patient*s best benefit. The dose level will start with
three patients. If none of the patients has experienced a DLT, a new dose level
may be started according to the percentages of the escalation rules of arm A.
If one patient has experienced a DLT, the dose level will be expanded to six
patients. If still less than two patients (out of six) have experienced a DLT,
a new dose level may be started according to the percentages of the escalation
rules of arm A. If two patients have experienced a DLT, a new dose level will
be started with a lower dose of docetaxel (to be determined by the principal
investigator after careful evaluation of safety and PK of the actual dose
level). Every dose level can be expanded to six patients, if less than 2 DLTs
have occurred. The final recommended dose for future phase II will be expanded
to a maximum of twelve patients.

- Patients participating will be hospitalized during the first and fifteenth
day and night. (Arm B: first, eighth and fifteenth day)
- Blood will be drawn for pharmacokinetic research, hematology, and serum
chemistry (see *Pharmacokinetics*).
- All patients will have to visit the hospital once every week and on day 3
and 17. After the first tumor evaluation, patient-visits will be once every two
weeks.
- Patients are at risk for docetaxel related side effects. Currently, a
comparable dose escalation study of weekly administration (once daily) of oral
ModraDoc001 in combination with ritonavir is ongoing at the NKI. Hitherto, the
highest dose which is proven tolerable, is 80 mg. According to preliminary
results the AUC is comparable with historical data of weekly IV administration
(35 mg/m2), but no severe (grade 3-4) hematologic adverse events have been seen
yet in the dose escalation.